Pleiotropic Effects of Kappa Opioid Receptor-Related Ligands in Non-human Primates
The kappa opioid receptor (KOR)-related ligands have been demonstrated in preclinical studies for several therapeutic potentials. This chapter highlights (1) how non-human primates (NHP) studies facilitate the research and development of ligands targeting
- PDF / 300,480 Bytes
- 18 Pages / 439.37 x 666.142 pts Page_size
- 72 Downloads / 171 Views
Contents 1 The Dynorphin-Kappa Opioid Receptor System 2 Effects of Dynorphins in Non-human Primates 3 Kappa Opioid Receptor Agonists as Antipruritics 3.1 Systemic Effects 3.2 Intrathecal Effects 4 Kappa Opioid Receptor Agonists as Analgesics 4.1 Centrally Acting Kappa Opioid Receptor Agonists 4.2 Peripherally Acting Kappa Opioid Receptor Agonists 5 Kappa Opioid Receptor-Related Ligands for the Treatment of Substance Use Disorders 5.1 Effects of Kappa Opioid Receptor-Related Agonists 5.2 Effects of Kappa Opioid Receptor Antagonists 6 Pleiotropic Effects of Kappa Opioid Receptor-Related Ligands 7 Conclusion References
Abstract
The kappa opioid receptor (KOR)-related ligands have been demonstrated in preclinical studies for several therapeutic potentials. This chapter highlights (1) how non-human primates (NHP) studies facilitate the research and development of ligands targeting the KOR, (2) effects of the endogenous opioid peptide, dynorphin A-(1-17), and its analogs in NHP, and (3) pleiotropic effects and therapeutic applications of KOR-related ligands. In particular, synthetic ligands
M.-C. Ko (*) Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA e-mail: [email protected] S. M. Husbands Department of Pharmacy & Pharmacology, University of Bath, Bath, UK # The Author(s), under exclusive license to Springer Nature Switzerland AG 2020 Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2020_419
M.-C. Ko and S. M. Husbands
targeting the KOR have been extensively studied in NHP in three therapeutic areas, i.e., the treatment for itch, pain, and substance use disorders. As the KORs are widely expressed in the peripheral and central nervous systems, pleiotropic effects of KOR-related ligands, such as discriminative stimulus effects, neuroendocrine effects (e.g., prolactin release and stimulation of hypothalamic-pituitaryadrenal axis), and diuresis, in NHP are discussed. Centrally acting KOR agonists are known to produce adverse effects including dysphoria, hallucination, and sedation. Nonetheless, with strategic advances in medicinal chemistry, three classes of KOR-related agonists, i.e., peripherally restricted KOR agonists, mixed KOR/mu opioid receptor partial agonists, and G protein-biased KOR agonists, warrant additional NHP studies to improve our understanding of their functional efficacy, selectivity, and tolerability. Pharmacological studies in NHP which carry high translational significance will facilitate future development of KOR-based medications. Keywords
Analgesics · Antipruritics · Drug abuse · Itch · Kappa opioid receptor · Macaque · Mu opioid receptor · Neuroendocrine function · Opioids · Pain · Spinal cord
1
The Dynorphin-Kappa Opioid Receptor System
In 1975, Avram Goldstein and his colleagues isolated and purified an endogenous opioid peptide named dynorphin A, a 17 amino acid polypeptide (Cox et al. 1975; Goldstein et al. 1981; Teschemacher et al. 1975). This peptide was described as “extraordinarily potent” (“dyn” from the Greek, dy
Data Loading...
